@article {6927, title = {Gene-Environment Interactions of Circadian-Related Genes for Cardiometabolic Traits.}, journal = {Diabetes Care}, volume = {38}, year = {2015}, month = {2015 Aug}, pages = {1456-66}, abstract = {

OBJECTIVE: Common circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153, MTNR1B-rs10830963, NR1D1-rs2314339) and cardiometabolic traits (fasting glucose [FG], HOMA-insulin resistance, BMI, waist circumference, and HDL-cholesterol) to facilitate personalized recommendations.

RESEARCH DESIGN AND METHODS: We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations and interactions between dietary intake/sleep duration and selected variants on cardiometabolic traits from 15 cohort studies including up to 28,190 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

RESULTS: We observed significant associations between relative macronutrient intakes and glycemic traits and short sleep duration (<7 h) and higher FG and replicated known MTNR1B associations with glycemic traits. No interactions were evident after accounting for multiple comparisons. However, we observed nominally significant interactions (all P < 0.01) between carbohydrate intake and MTNR1B-rs1387153 for FG with a 0.003 mmol/L higher FG with each additional 1\% carbohydrate intake in the presence of the T allele, between sleep duration and CRY2-rs11605924 for HDL-cholesterol with a 0.010 mmol/L higher HDL-cholesterol with each additional hour of sleep in the presence of the A allele, and between long sleep duration (>=9 h) and MTNR1B-rs1387153 for BMI with a 0.60 kg/m(2) higher BMI with long sleep duration in the presence of the T allele relative to normal sleep duration (>=7 to <9 h).

CONCLUSIONS: Our results suggest that lower carbohydrate intake and normal sleep duration may ameliorate cardiometabolic abnormalities conferred by common circadian-related genetic variants. Until further mechanistic examination of the nominally significant interactions is conducted, recommendations applicable to the general population regarding diet{\textemdash}specifically higher carbohydrate and lower fat composition{\textemdash}and normal sleep duration should continue to be emphasized among individuals with the investigated circadian-related gene variants.

}, keywords = {Adult, Alleles, Blood Glucose, Circadian Rhythm Signaling Peptides and Proteins, Cohort Studies, Diabetes Mellitus, Type 2, Diet, Fat-Restricted, European Continental Ancestry Group, Fasting, Female, Gene-Environment Interaction, Humans, Insulin Resistance, Male, Middle Aged, Multicenter Studies as Topic, Observational Studies as Topic, Phenotype, Polymorphism, Single Nucleotide, Sleep, Waist Circumference}, issn = {1935-5548}, doi = {10.2337/dc14-2709}, author = {Dashti, Hassan S and Follis, Jack L and Smith, Caren E and Tanaka, Toshiko and Garaulet, Marta and Gottlieb, Daniel J and Hruby, Adela and Jacques, Paul F and Kiefte-de Jong, Jessica C and Lamon-Fava, Stefania and Scheer, Frank A J L and Bartz, Traci M and Kovanen, Leena and Wojczynski, Mary K and Frazier-Wood, Alexis C and Ahluwalia, Tarunveer S and Per{\"a}l{\"a}, Mia-Maria and Jonsson, Anna and Muka, Taulant and Kalafati, Ioanna P and Mikkil{\"a}, Vera and Ordovas, Jose M} } @article {6936, title = {A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 Jan 15}, pages = {358-70}, abstract = {

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including \~{}120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3\% of the variance in plasma fibrinogen concentration.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddv454}, author = {de Vries, Paul S and Chasman, Daniel I and Sabater-Lleal, Maria and Chen, Ming-Huei and Huffman, Jennifer E and Steri, Maristella and Tang, Weihong and Teumer, Alexander and Marioni, Riccardo E and Grossmann, Vera and Hottenga, Jouke J and Trompet, Stella and M{\"u}ller-Nurasyid, Martina and Zhao, Jing Hua and Brody, Jennifer A and Kleber, Marcus E and Guo, Xiuqing and Wang, Jie Jin and Auer, Paul L and Attia, John R and Yanek, Lisa R and Ahluwalia, Tarunveer S and Lahti, Jari and Venturini, Cristina and Tanaka, Toshiko and Bielak, Lawrence F and Joshi, Peter K and Rocanin-Arjo, Ares and Kolcic, Ivana and Navarro, Pau and Rose, Lynda M and Oldmeadow, Christopher and Riess, Helene and Mazur, Johanna and Basu, Saonli and Goel, Anuj and Yang, Qiong and Ghanbari, Mohsen and Willemsen, Gonneke and Rumley, Ann and Fiorillo, Edoardo and de Craen, Anton J M and Grotevendt, Anne and Scott, Robert and Taylor, Kent D and Delgado, Graciela E and Yao, Jie and Kifley, Annette and Kooperberg, Charles and Qayyum, Rehan and Lopez, Lorna M and Berentzen, Tina L and R{\"a}ikk{\"o}nen, Katri and Mangino, Massimo and Bandinelli, Stefania and Peyser, Patricia A and Wild, Sarah and Tr{\'e}gou{\"e}t, David-Alexandre and Wright, Alan F and Marten, Jonathan and Zemunik, Tatijana and Morrison, Alanna C and Sennblad, Bengt and Tofler, Geoffrey and de Maat, Moniek P M and de Geus, Eco J C and Lowe, Gordon D and Zoledziewska, Magdalena and Sattar, Naveed and Binder, Harald and V{\"o}lker, Uwe and Waldenberger, Melanie and Khaw, Kay-Tee and McKnight, Barbara and Huang, Jie and Jenny, Nancy S and Holliday, Elizabeth G and Qi, Lihong and Mcevoy, Mark G and Becker, Diane M and Starr, John M and Sarin, Antti-Pekka and Hysi, Pirro G and Hernandez, Dena G and Jhun, Min A and Campbell, Harry and Hamsten, Anders and Rivadeneira, Fernando and McArdle, Wendy L and Slagboom, P Eline and Zeller, Tanja and Koenig, Wolfgang and Psaty, Bruce M and Haritunians, Talin and Liu, Jingmin and Palotie, Aarno and Uitterlinden, Andr{\'e} G and Stott, David J and Hofman, Albert and Franco, Oscar H and Polasek, Ozren and Rudan, Igor and Morange, Pierre-Emmanuel and Wilson, James F and Kardia, Sharon L R and Ferrucci, Luigi and Spector, Tim D and Eriksson, Johan G and Hansen, Torben and Deary, Ian J and Becker, Lewis C and Scott, Rodney J and Mitchell, Paul and M{\"a}rz, Winfried and Wareham, Nick J and Peters, Annette and Greinacher, Andreas and Wild, Philipp S and Jukema, J Wouter and Boomsma, Dorret I and Hayward, Caroline and Cucca, Francesco and Tracy, Russell and Watkins, Hugh and Reiner, Alex P and Folsom, Aaron R and Ridker, Paul M and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L and Strachan, David P and Dehghan, Abbas} } @article {8570, title = {A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape.}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016 11 23}, pages = {13357}, abstract = {

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99\% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

}, keywords = {Anthropometry, Body Size, Genome-Wide Association Study, Genotype, Humans, Models, Genetic, Principal Component Analysis}, issn = {2041-1723}, doi = {10.1038/ncomms13357}, author = {Ried, Janina S and Jeff M, Janina and Chu, Audrey Y and Bragg-Gresham, Jennifer L and van Dongen, Jenny and Huffman, Jennifer E and Ahluwalia, Tarunveer S and Cadby, Gemma and Eklund, Niina and Eriksson, Joel and Esko, T{\~o}nu and Feitosa, Mary F and Goel, Anuj and Gorski, Mathias and Hayward, Caroline and Heard-Costa, Nancy L and Jackson, Anne U and Jokinen, Eero and Kanoni, Stavroula and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Lahti, Jari and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Mahajan, Anubha and Mangino, Massimo and Medina-G{\'o}mez, Carolina and Monda, Keri L and Nolte, Ilja M and Perusse, Louis and Prokopenko, Inga and Qi, Lu and Rose, Lynda M and Salvi, Erika and Smith, Megan T and Snieder, Harold and Stan{\v c}{\'a}kov{\'a}, Alena and Ju Sung, Yun and Tachmazidou, Ioanna and Teumer, Alexander and Thorleifsson, Gudmar and van der Harst, Pim and Walker, Ryan W and Wang, Sophie R and Wild, Sarah H and Willems, Sara M and Wong, Andrew and Zhang, Weihua and Albrecht, Eva and Couto Alves, Alexessander and Bakker, Stephan J L and Barlassina, Cristina and Bartz, Traci M and Beilby, John and Bellis, Claire and Bergman, Richard N and Bergmann, Sven and Blangero, John and Bl{\"u}her, Matthias and Boerwinkle, Eric and Bonnycastle, Lori L and Bornstein, Stefan R and Bruinenberg, Marcel and Campbell, Harry and Chen, Yii-Der Ida and Chiang, Charleston W K and Chines, Peter S and Collins, Francis S and Cucca, Fracensco and Cupples, L Adrienne and D{\textquoteright}Avila, Francesca and de Geus, Eco J C and Dedoussis, George and Dimitriou, Maria and D{\"o}ring, Angela and Eriksson, Johan G and Farmaki, Aliki-Eleni and Farrall, Martin and Ferreira, Teresa and Fischer, Krista and Forouhi, Nita G and Friedrich, Nele and Gjesing, Anette Prior and Glorioso, Nicola and Graff, Mariaelisa and Grallert, Harald and Grarup, Niels and Gr{\"a}{\ss}ler, J{\"u}rgen and Grewal, Jagvir and Hamsten, Anders and Harder, Marie Neergaard and Hartman, Catharina A and Hassinen, Maija and Hastie, Nicholas and Hattersley, Andrew Tym and Havulinna, Aki S and Heli{\"o}vaara, Markku and Hillege, Hans and Hofman, Albert and Holmen, Oddgeir and Homuth, Georg and Hottenga, Jouke-Jan and Hui, Jennie and Husemoen, Lise Lotte and Hysi, Pirro G and Isaacs, Aaron and Ittermann, Till and Jalilzadeh, Shapour and James, Alan L and J{\o}rgensen, Torben and Jousilahti, Pekka and Jula, Antti and Marie Justesen, Johanne and Justice, Anne E and K{\"a}h{\"o}nen, Mika and Karaleftheri, Maria and Tee Khaw, Kay and Keinanen-Kiukaanniemi, Sirkka M and Kinnunen, Leena and Knekt, Paul B and Koistinen, Heikki A and Kolcic, Ivana and Kooner, Ishminder K and Koskinen, Seppo and Kovacs, Peter and Kyriakou, Theodosios and Laitinen, Tomi and Langenberg, Claudia and Lewin, Alexandra M and Lichtner, Peter and Lindgren, Cecilia M and Lindstr{\"o}m, Jaana and Linneberg, Allan and Lorbeer, Roberto and Lorentzon, Mattias and Luben, Robert and Lyssenko, Valeriya and M{\"a}nnist{\"o}, Satu and Manunta, Paolo and Leach, Irene Mateo and McArdle, Wendy L and McKnight, Barbara and Mohlke, Karen L and Mihailov, Evelin and Milani, Lili and Mills, Rebecca and Montasser, May E and Morris, Andrew P and M{\"u}ller, Gabriele and Musk, Arthur W and Narisu, Narisu and Ong, Ken K and Oostra, Ben A and Osmond, Clive and Palotie, Aarno and Pankow, James S and Paternoster, Lavinia and Penninx, Brenda W and Pichler, Irene and Pilia, Maria G and Polasek, Ozren and Pramstaller, Peter P and Raitakari, Olli T and Rankinen, Tuomo and Rao, D C and Rayner, Nigel W and Ribel-Madsen, Rasmus and Rice, Treva K and Richards, Marcus and Ridker, Paul M and Rivadeneira, Fernando and Ryan, Kathy A and Sanna, Serena and Sarzynski, Mark A and Scholtens, Salome and Scott, Robert A and Sebert, Sylvain and Southam, Lorraine and Spars{\o}, Thomas Hempel and Steinthorsdottir, Valgerdur and Stirrups, Kathleen and Stolk, Ronald P and Strauch, Konstantin and Stringham, Heather M and Swertz, Morris A and Swift, Amy J and T{\"o}njes, Anke and Tsafantakis, Emmanouil and van der Most, Peter J and van Vliet-Ostaptchouk, Jana V and Vandenput, Liesbeth and Vartiainen, Erkki and Venturini, Cristina and Verweij, Niek and Viikari, Jorma S and Vitart, Veronique and Vohl, Marie-Claude and Vonk, Judith M and Waeber, G{\'e}rard and Widen, Elisabeth and Willemsen, Gonneke and Wilsgaard, Tom and Winkler, Thomas W and Wright, Alan F and Yerges-Armstrong, Laura M and Hua Zhao, Jing and Zillikens, M Carola and Boomsma, Dorret I and Bouchard, Claude and Chambers, John C and Chasman, Daniel I and Cusi, Daniele and Gansevoort, Ron T and Gieger, Christian and Hansen, Torben and Hicks, Andrew A and Hu, Frank and Hveem, Kristian and Jarvelin, Marjo-Riitta and Kajantie, Eero and Kooner, Jaspal S and Kuh, Diana and Kuusisto, Johanna and Laakso, Markku and Lakka, Timo A and Lehtim{\"a}ki, Terho and Metspalu, Andres and Nj{\o}lstad, Inger and Ohlsson, Claes and Oldehinkel, Albertine J and Palmer, Lyle J and Pedersen, Oluf and Perola, Markus and Peters, Annette and Psaty, Bruce M and Puolijoki, Hannu and Rauramaa, Rainer and Rudan, Igor and Salomaa, Veikko and Schwarz, Peter E H and Shudiner, Alan R and Smit, Jan H and S{\o}rensen, Thorkild I A and Spector, Timothy D and Stefansson, Kari and Stumvoll, Michael and Tremblay, Angelo and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Uusitupa, Matti and V{\"o}lker, Uwe and Vollenweider, Peter and Wareham, Nicholas J and Watkins, Hugh and Wilson, James F and Zeggini, Eleftheria and Abecasis, Goncalo R and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and van Duijn, Cornelia M and Fox, Caroline and Groop, Leif C and Heid, Iris M and Hunter, David J and Kaplan, Robert C and McCarthy, Mark I and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Schlessinger, David and Thorsteinsdottir, Unnur and Strachan, David P and Frayling, Timothy and Hirschhorn, Joel N and M{\"u}ller-Nurasyid, Martina and Loos, Ruth J F} } @article {7255, title = {SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.}, journal = {J Am Soc Nephrol}, year = {2016}, month = {2016 Dec 05}, abstract = {

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7{\texttimes}10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4{\texttimes}10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

}, issn = {1533-3450}, doi = {10.1681/ASN.2016020131}, author = {Li, Man and Li, Yong and Weeks, Olivia and Mijatovic, Vladan and Teumer, Alexander and Huffman, Jennifer E and Tromp, Gerard and Fuchsberger, Christian and Gorski, Mathias and Lyytik{\"a}inen, Leo-Pekka and Nutile, Teresa and Sedaghat, Sanaz and Sorice, Rossella and Tin, Adrienne and Yang, Qiong and Ahluwalia, Tarunveer S and Arking, Dan E and Bihlmeyer, Nathan A and B{\"o}ger, Carsten A and Carroll, Robert J and Chasman, Daniel I and Cornelis, Marilyn C and Dehghan, Abbas and Faul, Jessica D and Feitosa, Mary F and Gambaro, Giovanni and Gasparini, Paolo and Giulianini, Franco and Heid, Iris and Huang, Jinyan and Imboden, Medea and Jackson, Anne U and Jeff, Janina and Jhun, Min A and Katz, Ronit and Kifley, Annette and Kilpel{\"a}inen, Tuomas O and Kumar, Ashish and Laakso, Markku and Li-Gao, Ruifang and Lohman, Kurt and Lu, Yingchang and M{\"a}gi, Reedik and Malerba, Giovanni and Mihailov, Evelin and Mohlke, Karen L and Mook-Kanamori, Dennis O and Robino, Antonietta and Ruderfer, Douglas and Salvi, Erika and Schick, Ursula M and Schulz, Christina-Alexandra and Smith, Albert V and Smith, Jennifer A and Traglia, Michela and Yerges-Armstrong, Laura M and Zhao, Wei and Goodarzi, Mark O and Kraja, Aldi T and Liu, Chunyu and Wessel, Jennifer and Boerwinkle, Eric and Borecki, Ingrid B and Bork-Jensen, Jette and Bottinger, Erwin P and Braga, Daniele and Brandslund, Ivan and Brody, Jennifer A and Campbell, Archie and Carey, David J and Christensen, Cramer and Coresh, Josef and Crook, Errol and Curhan, Gary C and Cusi, Daniele and de Boer, Ian H and de Vries, Aiko P J and Denny, Joshua C and Devuyst, Olivier and Dreisbach, Albert W and Endlich, Karlhans and Esko, T{\~o}nu and Franco, Oscar H and Fulop, Tibor and Gerhard, Glenn S and Gl{\"u}mer, Charlotte and Gottesman, Omri and Grarup, Niels and Gudnason, Vilmundur and Harris, Tamara B and Hayward, Caroline and Hocking, Lynne and Hofman, Albert and Hu, Frank B and Husemoen, Lise Lotte N and Jackson, Rebecca D and J{\o}rgensen, Torben and J{\o}rgensen, Marit E and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and K{\"o}nig, Wolfgang and Kooperberg, Charles and Kriebel, Jennifer and Launer, Lenore J and Lauritzen, Torsten and Lehtim{\"a}ki, Terho and Levy, Daniel and Linksted, Pamela and Linneberg, Allan and Liu, Yongmei and Loos, Ruth J F and Lupo, Antonio and Meisinger, Christine and Melander, Olle and Metspalu, Andres and Mitchell, Paul and Nauck, Matthias and N{\"u}rnberg, Peter and Orho-Melander, Marju and Parsa, Afshin and Pedersen, Oluf and Peters, Annette and Peters, Ulrike and Polasek, Ozren and Porteous, David and Probst-Hensch, Nicole M and Psaty, Bruce M and Qi, Lu and Raitakari, Olli T and Reiner, Alex P and Rettig, Rainer and Ridker, Paul M and Rivadeneira, Fernando and Rossouw, Jacques E and Schmidt, Frank and Siscovick, David and Soranzo, Nicole and Strauch, Konstantin and Toniolo, Daniela and Turner, Stephen T and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Velayutham, Dinesh and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Wang, Jie Jin and Weir, David R and Witte, Daniel and Kuivaniemi, Helena and Fox, Caroline S and Franceschini, Nora and Goessling, Wolfram and K{\"o}ttgen, Anna and Chu, Audrey Y} } @article {7343, title = {Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study.}, journal = {PLoS One}, volume = {12}, year = {2017}, month = {2017}, pages = {e0167742}, abstract = {

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5{\texttimes}10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5{\texttimes}10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20\% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0167742}, author = {de Vries, Paul S and Sabater-Lleal, Maria and Chasman, Daniel I and Trompet, Stella and Ahluwalia, Tarunveer S and Teumer, Alexander and Kleber, Marcus E and Chen, Ming-Huei and Wang, Jie Jin and Attia, John R and Marioni, Riccardo E and Steri, Maristella and Weng, Lu-Chen and Pool, Rene and Grossmann, Vera and Brody, Jennifer A and Venturini, Cristina and Tanaka, Toshiko and Rose, Lynda M and Oldmeadow, Christopher and Mazur, Johanna and Basu, Saonli and Fr{\r a}nberg, Mattias and Yang, Qiong and Ligthart, Symen and Hottenga, Jouke J and Rumley, Ann and Mulas, Antonella and de Craen, Anton J M and Grotevendt, Anne and Taylor, Kent D and Delgado, Graciela E and Kifley, Annette and Lopez, Lorna M and Berentzen, Tina L and Mangino, Massimo and Bandinelli, Stefania and Morrison, Alanna C and Hamsten, Anders and Tofler, Geoffrey and de Maat, Moniek P M and Draisma, Harmen H M and Lowe, Gordon D and Zoledziewska, Magdalena and Sattar, Naveed and Lackner, Karl J and V{\"o}lker, Uwe and McKnight, Barbara and Huang, Jie and Holliday, Elizabeth G and McEvoy, Mark A and Starr, John M and Hysi, Pirro G and Hernandez, Dena G and Guan, Weihua and Rivadeneira, Fernando and McArdle, Wendy L and Slagboom, P Eline and Zeller, Tanja and Psaty, Bruce M and Uitterlinden, Andr{\'e} G and de Geus, Eco J C and Stott, David J and Binder, Harald and Hofman, Albert and Franco, Oscar H and Rotter, Jerome I and Ferrucci, Luigi and Spector, Tim D and Deary, Ian J and M{\"a}rz, Winfried and Greinacher, Andreas and Wild, Philipp S and Cucca, Francesco and Boomsma, Dorret I and Watkins, Hugh and Tang, Weihong and Ridker, Paul M and Jukema, Jan W and Scott, Rodney J and Mitchell, Paul and Hansen, Torben and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L and Strachan, David P and Dehghan, Abbas} } @article {7920, title = {Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 Nov 01}, pages = {691-706}, abstract = {

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5~{\texttimes} 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0\% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.09.009}, author = {Ligthart, Symen and Vaez, Ahmad and V{\~o}sa, Urmo and Stathopoulou, Maria G and de Vries, Paul S and Prins, Bram P and van der Most, Peter J and Tanaka, Toshiko and Naderi, Elnaz and Rose, Lynda M and Wu, Ying and Karlsson, Robert and Barbalic, Maja and Lin, Honghuang and Pool, Rene and Zhu, Gu and Mace, Aurelien and Sidore, Carlo and Trompet, Stella and Mangino, Massimo and Sabater-Lleal, Maria and Kemp, John P and Abbasi, Ali and Kacprowski, Tim and Verweij, Niek and Smith, Albert V and Huang, Tao and Marzi, Carola and Feitosa, Mary F and Lohman, Kurt K and Kleber, Marcus E and Milaneschi, Yuri and Mueller, Christian and Huq, Mahmudul and Vlachopoulou, Efthymia and Lyytik{\"a}inen, Leo-Pekka and Oldmeadow, Christopher and Deelen, Joris and Perola, Markus and Zhao, Jing Hua and Feenstra, Bjarke and Amini, Marzyeh and Lahti, Jari and Schraut, Katharina E and Fornage, Myriam and Suktitipat, Bhoom and Chen, Wei-Min and Li, Xiaohui and Nutile, Teresa and Malerba, Giovanni and Luan, Jian{\textquoteright}an and Bak, Tom and Schork, Nicholas and del Greco M, Fabiola and Thiering, Elisabeth and Mahajan, Anubha and Marioni, Riccardo E and Mihailov, Evelin and Eriksson, Joel and Ozel, Ayse Bilge and Zhang, Weihua and Nethander, Maria and Cheng, Yu-Ching and Aslibekyan, Stella and Ang, Wei and Gandin, Ilaria and Yengo, Loic and Portas, Laura and Kooperberg, Charles and Hofer, Edith and Rajan, Kumar B and Schurmann, Claudia and den Hollander, Wouter and Ahluwalia, Tarunveer S and Zhao, Jing and Draisma, Harmen H M and Ford, Ian and Timpson, Nicholas and Teumer, Alexander and Huang, Hongyan and Wahl, Simone and Liu, Yongmei and Huang, Jie and Uh, Hae-Won and Geller, Frank and Joshi, Peter K and Yanek, Lisa R and Trabetti, Elisabetta and Lehne, Benjamin and Vozzi, Diego and Verbanck, Marie and Biino, Ginevra and Saba, Yasaman and Meulenbelt, Ingrid and O{\textquoteright}Connell, Jeff R and Laakso, Markku and Giulianini, Franco and Magnusson, Patrik K E and Ballantyne, Christie M and Hottenga, Jouke Jan and Montgomery, Grant W and Rivadineira, Fernando and Rueedi, Rico and Steri, Maristella and Herzig, Karl-Heinz and Stott, David J and Menni, Cristina and Fr{\r a}nberg, Mattias and St Pourcain, Beate and Felix, Stephan B and Pers, Tune H and Bakker, Stephan J L and Kraft, Peter and Peters, Annette and Vaidya, Dhananjay and Delgado, Graciela and Smit, Johannes H and Gro{\ss}mann, Vera and Sinisalo, Juha and Sepp{\"a}l{\"a}, Ilkka and Williams, Stephen R and Holliday, Elizabeth G and Moed, Matthijs and Langenberg, Claudia and R{\"a}ikk{\"o}nen, Katri and Ding, Jingzhong and Campbell, Harry and Sale, Mich{\`e}le M and Chen, Yii-der I and James, Alan L and Ruggiero, Daniela and Soranzo, Nicole and Hartman, Catharina A and Smith, Erin N and Berenson, Gerald S and Fuchsberger, Christian and Hernandez, Dena and Tiesler, Carla M T and Giedraitis, Vilmantas and Liewald, David and Fischer, Krista and Mellstr{\"o}m, Dan and Larsson, Anders and Wang, Yunmei and Scott, William R and Lorentzon, Matthias and Beilby, John and Ryan, Kathleen A and Pennell, Craig E and Vuckovic, Dragana and Balkau, Beverly and Concas, Maria Pina and Schmidt, Reinhold and Mendes de Leon, Carlos F and Bottinger, Erwin P and Kloppenburg, Margreet and Paternoster, Lavinia and Boehnke, Michael and Musk, A W and Willemsen, Gonneke and Evans, David M and Madden, Pamela A F and K{\"a}h{\"o}nen, Mika and Kutalik, Zolt{\'a}n and Zoledziewska, Magdalena and Karhunen, Ville and Kritchevsky, Stephen B and Sattar, Naveed and Lachance, Genevieve and Clarke, Robert and Harris, Tamara B and Raitakari, Olli T and Attia, John R and van Heemst, Diana and Kajantie, Eero and Sorice, Rossella and Gambaro, Giovanni and Scott, Robert A and Hicks, Andrew A and Ferrucci, Luigi and Standl, Marie and Lindgren, Cecilia M and Starr, John M and Karlsson, Magnus and Lind, Lars and Li, Jun Z and Chambers, John C and Mori, Trevor A and de Geus, Eco J C N and Heath, Andrew C and Martin, Nicholas G and Auvinen, Juha and Buckley, Brendan M and de Craen, Anton J M and Waldenberger, Melanie and Strauch, Konstantin and Meitinger, Thomas and Scott, Rodney J and McEvoy, Mark and Beekman, Marian and Bombieri, Cristina and Ridker, Paul M and Mohlke, Karen L and Pedersen, Nancy L and Morrison, Alanna C and Boomsma, Dorret I and Whitfield, John B and Strachan, David P and Hofman, Albert and Vollenweider, Peter and Cucca, Francesco and Jarvelin, Marjo-Riitta and Jukema, J Wouter and Spector, Tim D and Hamsten, Anders and Zeller, Tanja and Uitterlinden, Andr{\'e} G and Nauck, Matthias and Gudnason, Vilmundur and Qi, Lu and Grallert, Harald and Borecki, Ingrid B and Rotter, Jerome I and M{\"a}rz, Winfried and Wild, Philipp S and Lokki, Marja-Liisa and Boyle, Michael and Salomaa, Veikko and Melbye, Mads and Eriksson, Johan G and Wilson, James F and Penninx, Brenda W J H and Becker, Diane M and Worrall, Bradford B and Gibson, Greg and Krauss, Ronald M and Ciullo, Marina and Zaza, Gianluigi and Wareham, Nicholas J and Oldehinkel, Albertine J and Palmer, Lyle J and Murray, Sarah S and Pramstaller, Peter P and Bandinelli, Stefania and Heinrich, Joachim and Ingelsson, Erik and Deary, Ian J and M{\"a}gi, Reedik and Vandenput, Liesbeth and van der Harst, Pim and Desch, Karl C and Kooner, Jaspal S and Ohlsson, Claes and Hayward, Caroline and Lehtim{\"a}ki, Terho and Shuldiner, Alan R and Arnett, Donna K and Beilin, Lawrence J and Robino, Antonietta and Froguel, Philippe and Pirastu, Mario and Jess, Tine and Koenig, Wolfgang and Loos, Ruth J F and Evans, Denis A and Schmidt, Helena and Smith, George Davey and Slagboom, P Eline and Eiriksdottir, Gudny and Morris, Andrew P and Psaty, Bruce M and Tracy, Russell P and Nolte, Ilja M and Boerwinkle, Eric and Visvikis-Siest, Sophie and Reiner, Alex P and Gross, Myron and Bis, Joshua C and Franke, Lude and Franco, Oscar H and Benjamin, Emelia J and Chasman, Daniel I and Dupuis, Jos{\'e}e and Snieder, Harold and Dehghan, Abbas and Alizadeh, Behrooz Z} } @article {7927, title = {Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 10 26}, pages = {4455}, abstract = {

Thyroid dysfunction is an important public health problem, which affects 10\% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves{\textquoteright} disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-06356-1}, author = {Teumer, Alexander and Chaker, Layal and Groeneweg, Stefan and Li, Yong and Di Munno, Celia and Barbieri, Caterina and Schultheiss, Ulla T and Traglia, Michela and Ahluwalia, Tarunveer S and Akiyama, Masato and Appel, Emil Vincent R and Arking, Dan E and Arnold, Alice and Astrup, Arne and Beekman, Marian and Beilby, John P and Bekaert, Sofie and Boerwinkle, Eric and Brown, Suzanne J and De Buyzere, Marc and Campbell, Purdey J and Ceresini, Graziano and Cerqueira, Charlotte and Cucca, Francesco and Deary, Ian J and Deelen, Joris and Eckardt, Kai-Uwe and Ekici, Arif B and Eriksson, Johan G and Ferrrucci, Luigi and Fiers, Tom and Fiorillo, Edoardo and Ford, Ian and Fox, Caroline S and Fuchsberger, Christian and Galesloot, Tessel E and Gieger, Christian and G{\"o}gele, Martin and De Grandi, Alessandro and Grarup, Niels and Greiser, Karin Halina and Haljas, Kadri and Hansen, Torben and Harris, Sarah E and van Heemst, Diana and den Heijer, Martin and Hicks, Andrew A and den Hollander, Wouter and Homuth, Georg and Hui, Jennie and Ikram, M Arfan and Ittermann, Till and Jensen, Richard A and Jing, Jiaojiao and Jukema, J Wouter and Kajantie, Eero and Kamatani, Yoichiro and Kasbohm, Elisa and Kaufman, Jean-Marc and Kiemeney, Lambertus A and Kloppenburg, Margreet and Kronenberg, Florian and Kubo, Michiaki and Lahti, Jari and Lapauw, Bruno and Li, Shuo and Liewald, David C M and Lim, Ee Mun and Linneberg, Allan and Marina, Michela and Mascalzoni, Deborah and Matsuda, Koichi and Medenwald, Daniel and Meisinger, Christa and Meulenbelt, Ingrid and De Meyer, Tim and Meyer zu Schwabedissen, Henriette E and Mikolajczyk, Rafael and Moed, Matthijs and Netea-Maier, Romana T and Nolte, Ilja M and Okada, Yukinori and Pala, Mauro and Pattaro, Cristian and Pedersen, Oluf and Petersmann, Astrid and Porcu, Eleonora and Postmus, Iris and Pramstaller, Peter P and Psaty, Bruce M and Ramos, Yolande F M and Rawal, Rajesh and Redmond, Paul and Richards, J Brent and Rietzschel, Ernst R and Rivadeneira, Fernando and Roef, Greet and Rotter, Jerome I and Sala, Cinzia F and Schlessinger, David and Selvin, Elizabeth and Slagboom, P Eline and Soranzo, Nicole and S{\o}rensen, Thorkild I A and Spector, Timothy D and Starr, John M and Stott, David J and Taes, Youri and Taliun, Daniel and Tanaka, Toshiko and Thuesen, Betina and Tiller, Daniel and Toniolo, Daniela and Uitterlinden, Andr{\'e} G and Visser, W Edward and Walsh, John P and Wilson, Scott G and Wolffenbuttel, Bruce H R and Yang, Qiong and Zheng, Hou-Feng and Cappola, Anne and Peeters, Robin P and Naitza, Silvia and V{\"o}lzke, Henry and Sanna, Serena and K{\"o}ttgen, Anna and Visser, Theo J and Medici, Marco} } @article {7795, title = {Meta-analysis of exome array data identifies six novel genetic loci for lung function.}, journal = {Wellcome Open Res}, volume = {3}, year = {2018}, month = {2018}, pages = {4}, abstract = {

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2{\textperiodcentered}8x10 ) associations with six SNPs: a nonsynonymous variant in , which is predicted to be damaging, three intronic SNPs ( and ) and two intergenic SNPs near to and Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including and . Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

}, issn = {2398-502X}, doi = {10.12688/wellcomeopenres.12583.3}, author = {Jackson, Victoria E and Latourelle, Jeanne C and Wain, Louise V and Smith, Albert V and Grove, Megan L and Bartz, Traci M and Obeidat, Ma{\textquoteright}en and Province, Michael A and Gao, Wei and Qaiser, Beenish and Porteous, David J and Cassano, Patricia A and Ahluwalia, Tarunveer S and Grarup, Niels and Li, Jin and Altmaier, Elisabeth and Marten, Jonathan and Harris, Sarah E and Manichaikul, Ani and Pottinger, Tess D and Li-Gao, Ruifang and Lind-Thomsen, Allan and Mahajan, Anubha and Lahousse, Lies and Imboden, Medea and Teumer, Alexander and Prins, Bram and Lyytik{\"a}inen, Leo-Pekka and Eiriksdottir, Gudny and Franceschini, Nora and Sitlani, Colleen M and Brody, Jennifer A and Boss{\'e}, Yohan and Timens, Wim and Kraja, Aldi and Loukola, Anu and Tang, Wenbo and Liu, Yongmei and Bork-Jensen, Jette and Justesen, Johanne M and Linneberg, Allan and Lange, Leslie A and Rawal, Rajesh and Karrasch, Stefan and Huffman, Jennifer E and Smith, Blair H and Davies, Gail and Burkart, Kristin M and Mychaleckyj, Josyf C and Bonten, Tobias N and Enroth, Stefan and Lind, Lars and Brusselle, Guy G and Kumar, Ashish and Stubbe, Beate and K{\"a}h{\"o}nen, Mika and Wyss, Annah B and Psaty, Bruce M and Heckbert, Susan R and Hao, Ke and Rantanen, Taina and Kritchevsky, Stephen B and Lohman, Kurt and Skaaby, Tea and Pisinger, Charlotta and Hansen, Torben and Schulz, Holger and Polasek, Ozren and Campbell, Archie and Starr, John M and Rich, Stephen S and Mook-Kanamori, Dennis O and Johansson, Asa and Ingelsson, Erik and Uitterlinden, Andr{\'e} G and Weiss, Stefan and Raitakari, Olli T and Gudnason, Vilmundur and North, Kari E and Gharib, Sina A and Sin, Don D and Taylor, Kent D and O{\textquoteright}Connor, George T and Kaprio, Jaakko and Harris, Tamara B and Pederson, Oluf and Vestergaard, Henrik and Wilson, James G and Strauch, Konstantin and Hayward, Caroline and Kerr, Shona and Deary, Ian J and Barr, R Graham and de Mutsert, Ren{\'e}e and Gyllensten, Ulf and Morris, Andrew P and Ikram, M Arfan and Probst-Hensch, Nicole and Gl{\"a}ser, Sven and Zeggini, Eleftheria and Lehtim{\"a}ki, Terho and Strachan, David P and Dupuis, Jos{\'e}e and Morrison, Alanna C and Hall, Ian P and Tobin, Martin D and London, Stephanie J} } @article {7819, title = {Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Jul 30}, pages = {2976}, abstract = {

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-05369-0}, author = {Wyss, Annah B and Sofer, Tamar and Lee, Mi Kyeong and Terzikhan, Natalie and Nguyen, Jennifer N and Lahousse, Lies and Latourelle, Jeanne C and Smith, Albert Vernon and Bartz, Traci M and Feitosa, Mary F and Gao, Wei and Ahluwalia, Tarunveer S and Tang, Wenbo and Oldmeadow, Christopher and Duan, Qing and de Jong, Kim and Wojczynski, Mary K and Wang, Xin-Qun and Noordam, Raymond and Hartwig, Fernando Pires and Jackson, Victoria E and Wang, Tianyuan and Obeidat, Ma{\textquoteright}en and Hobbs, Brian D and Huan, Tianxiao and Gui, Hongsheng and Parker, Margaret M and Hu, Donglei and Mogil, Lauren S and Kichaev, Gleb and Jin, Jianping and Graff, Mariaelisa and Harris, Tamara B and Kalhan, Ravi and Heckbert, Susan R and Paternoster, Lavinia and Burkart, Kristin M and Liu, Yongmei and Holliday, Elizabeth G and Wilson, James G and Vonk, Judith M and Sanders, Jason L and Barr, R Graham and de Mutsert, Ren{\'e}e and Menezes, Ana Maria Baptista and Adams, Hieab H H and van den Berge, Maarten and Joehanes, Roby and Levin, Albert M and Liberto, Jennifer and Launer, Lenore J and Morrison, Alanna C and Sitlani, Colleen M and Celed{\'o}n, Juan C and Kritchevsky, Stephen B and Scott, Rodney J and Christensen, Kaare and Rotter, Jerome I and Bonten, Tobias N and Wehrmeister, Fernando C{\'e}sar and Boss{\'e}, Yohan and Xiao, Shujie and Oh, Sam and Franceschini, Nora and Brody, Jennifer A and Kaplan, Robert C and Lohman, Kurt and McEvoy, Mark and Province, Michael A and Rosendaal, Frits R and Taylor, Kent D and Nickle, David C and Williams, L Keoki and Burchard, Esteban G and Wheeler, Heather E and Sin, Don D and Gudnason, Vilmundur and North, Kari E and Fornage, Myriam and Psaty, Bruce M and Myers, Richard H and O{\textquoteright}Connor, George and Hansen, Torben and Laurie, Cathy C and Cassano, Patricia A and Sung, Joohon and Kim, Woo Jin and Attia, John R and Lange, Leslie and Boezen, H Marike and Thyagarajan, Bharat and Rich, Stephen S and Mook-Kanamori, Dennis O and Horta, Bernardo Lessa and Uitterlinden, Andr{\'e} G and Im, Hae Kyung and Cho, Michael H and Brusselle, Guy G and Gharib, Sina A and Dupuis, Jos{\'e}e and Manichaikul, Ani and London, Stephanie J} } @article {8109, title = {A catalog of genetic loci associated with kidney function from analyses of a million individuals.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 06}, pages = {957-972}, abstract = {

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

}, keywords = {Chromosome Mapping, European Continental Ancestry Group, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Inheritance Patterns, Kidney Function Tests, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Renal Insufficiency, Chronic, Uromodulin}, issn = {1546-1718}, doi = {10.1038/s41588-019-0407-x}, author = {Wuttke, Matthias and Li, Yong and Li, Man and Sieber, Karsten B and Feitosa, Mary F and Gorski, Mathias and Tin, Adrienne and Wang, Lihua and Chu, Audrey Y and Hoppmann, Anselm and Kirsten, Holger and Giri, Ayush and Chai, Jin-Fang and Sveinbjornsson, Gardar and Tayo, Bamidele O and Nutile, Teresa and Fuchsberger, Christian and Marten, Jonathan and Cocca, Massimiliano and Ghasemi, Sahar and Xu, Yizhe and Horn, Katrin and Noce, Damia and van der Most, Peter J and Sedaghat, Sanaz and Yu, Zhi and Akiyama, Masato and Afaq, Saima and Ahluwalia, Tarunveer S and Almgren, Peter and Amin, Najaf and Arnl{\"o}v, Johan and Bakker, Stephan J L and Bansal, Nisha and Baptista, Daniela and Bergmann, Sven and Biggs, Mary L and Biino, Ginevra and Boehnke, Michael and Boerwinkle, Eric and Boissel, Mathilde and Bottinger, Erwin P and Boutin, Thibaud S and Brenner, Hermann and Brumat, Marco and Burkhardt, Ralph and Butterworth, Adam S and Campana, Eric and Campbell, Archie and Campbell, Harry and Canouil, Micka{\"e}l and Carroll, Robert J and Catamo, Eulalia and Chambers, John C and Chee, Miao-Ling and Chee, Miao-Li and Chen, Xu and Cheng, Ching-Yu and Cheng, Yurong and Christensen, Kaare and Cifkova, Renata and Ciullo, Marina and Concas, Maria Pina and Cook, James P and Coresh, Josef and Corre, Tanguy and Sala, Cinzia Felicita and Cusi, Daniele and Danesh, John and Daw, E Warwick and de Borst, Martin H and De Grandi, Alessandro and de Mutsert, Ren{\'e}e and de Vries, Aiko P J and Degenhardt, Frauke and Delgado, Graciela and Demirkan, Ayse and Di Angelantonio, Emanuele and Dittrich, Katalin and Divers, Jasmin and Dorajoo, Rajkumar and Eckardt, Kai-Uwe and Ehret, Georg and Elliott, Paul and Endlich, Karlhans and Evans, Michele K and Felix, Janine F and Foo, Valencia Hui Xian and Franco, Oscar H and Franke, Andre and Freedman, Barry I and Freitag-Wolf, Sandra and Friedlander, Yechiel and Froguel, Philippe and Gansevoort, Ron T and Gao, He and Gasparini, Paolo and Gaziano, J Michael and Giedraitis, Vilmantas and Gieger, Christian and Girotto, Giorgia and Giulianini, Franco and G{\"o}gele, Martin and Gordon, Scott D and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Haller, Toomas and Hamet, Pavel and Harris, Tamara B and Hartman, Catharina A and Hayward, Caroline and Hellwege, Jacklyn N and Heng, Chew-Kiat and Hicks, Andrew A and Hofer, Edith and Huang, Wei and Hutri-K{\"a}h{\"o}nen, Nina and Hwang, Shih-Jen and Ikram, M Arfan and Indridason, Olafur S and Ingelsson, Erik and Ising, Marcus and Jaddoe, Vincent W V and Jakobsdottir, Johanna and Jonas, Jost B and Joshi, Peter K and Josyula, Navya Shilpa and Jung, Bettina and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kammerer, Candace M and Kanai, Masahiro and Kastarinen, Mika and Kerr, Shona M and Khor, Chiea-Chuen and Kiess, Wieland and Kleber, Marcus E and Koenig, Wolfgang and Kooner, Jaspal S and K{\"o}rner, Antje and Kovacs, Peter and Kraja, Aldi T and Krajcoviechova, Alena and Kramer, Holly and Kr{\"a}mer, Bernhard K and Kronenberg, Florian and Kubo, Michiaki and Kuhnel, Brigitte and Kuokkanen, Mikko and Kuusisto, Johanna and La Bianca, Martina and Laakso, Markku and Lange, Leslie A and Langefeld, Carl D and Lee, Jeannette Jen-Mai and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Lieb, Wolfgang and Lim, Su-Chi and Lind, Lars and Lindgren, Cecilia M and Liu, Jun and Liu, Jianjun and Loeffler, Markus and Loos, Ruth J F and Lucae, Susanne and Lukas, Mary Ann and Lyytik{\"a}inen, Leo-Pekka and M{\"a}gi, Reedik and Magnusson, Patrik K E and Mahajan, Anubha and Martin, Nicholas G and Martins, Jade and M{\"a}rz, Winfried and Mascalzoni, Deborah and Matsuda, Koichi and Meisinger, Christa and Meitinger, Thomas and Melander, Olle and Metspalu, Andres and Mikaelsdottir, Evgenia K and Milaneschi, Yuri and Miliku, Kozeta and Mishra, Pashupati P and Mohlke, Karen L and Mononen, Nina and Montgomery, Grant W and Mook-Kanamori, Dennis O and Mychaleckyj, Josyf C and Nadkarni, Girish N and Nalls, Mike A and Nauck, Matthias and Nikus, Kjell and Ning, Boting and Nolte, Ilja M and Noordam, Raymond and O{\textquoteright}Connell, Jeffrey and O{\textquoteright}Donoghue, Michelle L and Olafsson, Isleifur and Oldehinkel, Albertine J and Orho-Melander, Marju and Ouwehand, Willem H and Padmanabhan, Sandosh and Palmer, Nicholette D and Palsson, Runolfur and Penninx, Brenda W J H and Perls, Thomas and Perola, Markus and Pirastu, Mario and Pirastu, Nicola and Pistis, Giorgio and Podgornaia, Anna I and Polasek, Ozren and Ponte, Belen and Porteous, David J and Poulain, Tanja and Pramstaller, Peter P and Preuss, Michael H and Prins, Bram P and Province, Michael A and Rabelink, Ton J and Raffield, Laura M and Raitakari, Olli T and Reilly, Dermot F and Rettig, Rainer and Rheinberger, Myriam and Rice, Kenneth M and Ridker, Paul M and Rivadeneira, Fernando and Rizzi, Federica and Roberts, David J and Robino, Antonietta and Rossing, Peter and Rudan, Igor and Rueedi, Rico and Ruggiero, Daniela and Ryan, Kathleen A and Saba, Yasaman and Sabanayagam, Charumathi and Salomaa, Veikko and Salvi, Erika and Saum, Kai-Uwe and Schmidt, Helena and Schmidt, Reinhold and Sch{\"o}ttker, Ben and Schulz, Christina-Alexandra and Schupf, Nicole and Shaffer, Christian M and Shi, Yuan and Smith, Albert V and Smith, Blair H and Soranzo, Nicole and Spracklen, Cassandra N and Strauch, Konstantin and Stringham, Heather M and Stumvoll, Michael and Svensson, Per O and Szymczak, Silke and Tai, E-Shyong and Tajuddin, Salman M and Tan, Nicholas Y Q and Taylor, Kent D and Teren, Andrej and Tham, Yih-Chung and Thiery, Joachim and Thio, Chris H L and Thomsen, Hauke and Thorleifsson, Gudmar and Toniolo, Daniela and T{\"o}njes, Anke and Tremblay, Johanne and Tzoulaki, Ioanna and Uitterlinden, Andr{\'e} G and Vaccargiu, Simona and van Dam, Rob M and van der Harst, Pim and van Duijn, Cornelia M and Velez Edward, Digna R and Verweij, Niek and Vogelezang, Suzanne and V{\"o}lker, Uwe and Vollenweider, Peter and Waeber, G{\'e}rard and Waldenberger, Melanie and Wallentin, Lars and Wang, Ya Xing and Wang, Chaolong and Waterworth, Dawn M and Bin Wei, Wen and White, Harvey and Whitfield, John B and Wild, Sarah H and Wilson, James F and Wojczynski, Mary K and Wong, Charlene and Wong, Tien-Yin and Xu, Liang and Yang, Qiong and Yasuda, Masayuki and Yerges-Armstrong, Laura M and Zhang, Weihua and Zonderman, Alan B and Rotter, Jerome I and Bochud, Murielle and Psaty, Bruce M and Vitart, Veronique and Wilson, James G and Dehghan, Abbas and Parsa, Afshin and Chasman, Daniel I and Ho, Kevin and Morris, Andrew P and Devuyst, Olivier and Akilesh, Shreeram and Pendergrass, Sarah A and Sim, Xueling and B{\"o}ger, Carsten A and Okada, Yukinori and Edwards, Todd L and Snieder, Harold and Stefansson, Kari and Hung, Adriana M and Heid, Iris M and Scholz, Markus and Teumer, Alexander and K{\"o}ttgen, Anna and Pattaro, Cristian} } @article {9372, title = {Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.}, journal = {Am J Hypertens}, volume = {32}, year = {2019}, month = {2019 Nov 15}, pages = {1146-1153}, abstract = {

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.

METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP >= 140 mm Hg and/or diastolic BP >= 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.

RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 {\texttimes} 10-8) and in the race-combined analysis (P = 1.5 {\texttimes} 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95\% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.

CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

}, keywords = {Aged, Antihypertensive Agents, Black or African American, Blood Pressure, Case-Control Studies, DNA (Cytosine-5-)-Methyltransferases, DNA Methyltransferase 3A, DNA-Binding Proteins, Drug Resistance, Dystrophin-Associated Proteins, Europe, Female, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Male, Middle Aged, Myosin Heavy Chains, Myosin Type V, Neuropeptides, Pharmacogenetics, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Transcription Factors, United States, White People}, issn = {1941-7225}, doi = {10.1093/ajh/hpz150}, author = {Irvin, Marguerite R and Sitlani, Colleen M and Floyd, James S and Psaty, Bruce M and Bis, Joshua C and Wiggins, Kerri L and Whitsel, Eric A and St{\"u}rmer, Til and Stewart, James and Raffield, Laura and Sun, Fangui and Liu, Ching-Ti and Xu, Hanfei and Cupples, Adrienne L and Tanner, Rikki M and Rossing, Peter and Smith, Albert and Zilh{\~a}o, Nuno R and Launer, Lenore J and Noordam, Raymond and Rotter, Jerome I and Yao, Jie and Li, Xiaohui and Guo, Xiuqing and Limdi, Nita and Sundaresan, Aishwarya and Lange, Leslie and Correa, Adolfo and Stott, David J and Ford, Ian and Jukema, J Wouter and Gudnason, Vilmundur and Mook-Kanamori, Dennis O and Trompet, Stella and Palmas, Walter and Warren, Helen R and Hellwege, Jacklyn N and Giri, Ayush and O{\textquoteright}donnell, Christopher and Hung, Adriana M and Edwards, Todd L and Ahluwalia, Tarunveer S and Arnett, Donna K and Avery, Christy L} } @article {8410, title = {Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood.}, journal = {Eur J Epidemiol}, volume = {35}, year = {2020}, month = {2020 Jul}, pages = {685-697}, abstract = {

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95\% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95\% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = - 0.76, 95\% CI - 2.45 to 1.08~mmHg), 0.06~mmHg lower diastolic blood pressure (β = - 0.06, 95\% CI - 0.93 to 0.87~mmHg), or pulse pressure (β = - 0.65, 95\% CI - 1.38 to 0.69~mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.

}, issn = {1573-7284}, doi = {10.1007/s10654-020-00638-z}, author = {Zheng, Yan and Huang, Tao and Wang, Tiange and Mei, Zhendong and Sun, Zhonghan and Zhang, Tao and Ellervik, Christina and Chai, Jin-Fang and Sim, Xueling and van Dam, Rob M and Tai, E-Shyong and Koh, Woon-Puay and Dorajoo, Rajkumar and Saw, Seang-Mei and Sabanayagam, Charumathi and Wong, Tien Yin and Gupta, Preeti and Rossing, Peter and Ahluwalia, Tarunveer S and Vinding, Rebecca K and Bisgaard, Hans and B{\o}nnelykke, Klaus and Wang, Yujie and Graff, Mariaelisa and Voortman, Trudy and van Rooij, Frank J A and Hofman, Albert and van Heemst, Diana and Noordam, Raymond and Estampador, Angela C and Varga, Tibor V and Enzenbach, Cornelia and Scholz, Markus and Thiery, Joachim and Burkhardt, Ralph and Orho-Melander, Marju and Schulz, Christina-Alexandra and Ericson, Ulrika and Sonestedt, Emily and Kubo, Michiaki and Akiyama, Masato and Zhou, Ang and Kilpel{\"a}inen, Tuomas O and Hansen, Torben and Kleber, Marcus E and Delgado, Graciela and McCarthy, Mark and Lemaitre, Rozenn N and Felix, Janine F and Jaddoe, Vincent W V and Wu, Ying and Mohlke, Karen L and Lehtim{\"a}ki, Terho and Wang, Carol A and Pennell, Craig E and Schunkert, Heribert and Kessler, Thorsten and Zeng, Lingyao and Willenborg, Christina and Peters, Annette and Lieb, Wolfgang and Grote, Veit and Rzehak, Peter and Koletzko, Berthold and Erdmann, Jeanette and Munz, Matthias and Wu, Tangchun and He, Meian and Yu, Caizheng and Lecoeur, C{\'e}cile and Froguel, Philippe and Corella, Dolores and Moreno, Luis A and Lai, Chao-Qiang and Pitk{\"a}nen, Niina and Boreham, Colin A and Ridker, Paul M and Rosendaal, Frits R and de Mutsert, Ren{\'e}e and Power, Chris and Paternoster, Lavinia and S{\o}rensen, Thorkild I A and Tj{\o}nneland, Anne and Overvad, Kim and Djouss{\'e}, Luc and Rivadeneira, Fernando and Lee, Nanette R and Raitakari, Olli T and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Langhendries, Jean-Paul and Escribano, Joaquin and Verduci, Elvira and Dedoussis, George and K{\"o}nig, Inke and Balkau, Beverley and Coltell, Oscar and Dallongeville, Jean and Meirhaeghe, Aline and Amouyel, Philippe and Gottrand, Fr{\'e}d{\'e}ric and Pahkala, Katja and Niinikoski, Harri and Hypp{\"o}nen, Elina and M{\"a}rz, Winfried and Mackey, David A and Gruszfeld, Dariusz and Tucker, Katherine L and Fumeron, Fr{\'e}d{\'e}ric and Estruch, Ramon and Ordovas, Jose M and Arnett, Donna K and Mook-Kanamori, Dennis O and Mozaffarian, Dariush and Psaty, Bruce M and North, Kari E and Chasman, Daniel I and Qi, Lu} } @article {8624, title = {Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.}, journal = {Kidney Int}, year = {2020}, month = {2020 Oct 30}, abstract = {

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25\% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95\% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

}, issn = {1523-1755}, doi = {10.1016/j.kint.2020.09.030}, author = {Gorski, Mathias and Jung, Bettina and Li, Yong and Matias-Garcia, Pamela R and Wuttke, Matthias and Coassin, Stefan and Thio, Chris H L and Kleber, Marcus E and Winkler, Thomas W and Wanner, Veronika and Chai, Jin-Fang and Chu, Audrey Y and Cocca, Massimiliano and Feitosa, Mary F and Ghasemi, Sahar and Hoppmann, Anselm and Horn, Katrin and Li, Man and Nutile, Teresa and Scholz, Markus and Sieber, Karsten B and Teumer, Alexander and Tin, Adrienne and Wang, Judy and Tayo, Bamidele O and Ahluwalia, Tarunveer S and Almgren, Peter and Bakker, Stephan J L and Banas, Bernhard and Bansal, Nisha and Biggs, Mary L and Boerwinkle, Eric and Bottinger, Erwin P and Brenner, Hermann and Carroll, Robert J and Chalmers, John and Chee, Miao-Li and Chee, Miao-Ling and Cheng, Ching-Yu and Coresh, Josef and de Borst, Martin H and Degenhardt, Frauke and Eckardt, Kai-Uwe and Endlich, Karlhans and Franke, Andre and Freitag-Wolf, Sandra and Gampawar, Piyush and Gansevoort, Ron T and Ghanbari, Mohsen and Gieger, Christian and Hamet, Pavel and Ho, Kevin and Hofer, Edith and Holleczek, Bernd and Xian Foo, Valencia Hui and Hutri-K{\"a}h{\"o}nen, Nina and Hwang, Shih-Jen and Ikram, M Arfan and Josyula, Navya Shilpa and K{\"a}h{\"o}nen, Mika and Khor, Chiea-Chuen and Koenig, Wolfgang and Kramer, Holly and Kr{\"a}mer, Bernhard K and Kuhnel, Brigitte and Lange, Leslie A and Lehtim{\"a}ki, Terho and Lieb, Wolfgang and Loos, Ruth J F and Lukas, Mary Ann and Lyytik{\"a}inen, Leo-Pekka and Meisinger, Christa and Meitinger, Thomas and Melander, Olle and Milaneschi, Yuri and Mishra, Pashupati P and Mononen, Nina and Mychaleckyj, Josyf C and Nadkarni, Girish N and Nauck, Matthias and Nikus, Kjell and Ning, Boting and Nolte, Ilja M and O{\textquoteright}Donoghue, Michelle L and Orho-Melander, Marju and Pendergrass, Sarah A and Penninx, Brenda W J H and Preuss, Michael H and Psaty, Bruce M and Raffield, Laura M and Raitakari, Olli T and Rettig, Rainer and Rheinberger, Myriam and Rice, Kenneth M and Rosenkranz, Alexander R and Rossing, Peter and Rotter, Jerome I and Sabanayagam, Charumathi and Schmidt, Helena and Schmidt, Reinhold and Sch{\"o}ttker, Ben and Schulz, Christina-Alexandra and Sedaghat, Sanaz and Shaffer, Christian M and Strauch, Konstantin and Szymczak, Silke and Taylor, Kent D and Tremblay, Johanne and Chaker, Layal and van der Harst, Pim and van der Most, Peter J and Verweij, Niek and V{\"o}lker, Uwe and Waldenberger, Melanie and Wallentin, Lars and Waterworth, Dawn M and White, Harvey D and Wilson, James G and Wong, Tien-Yin and Woodward, Mark and Yang, Qiong and Yasuda, Masayuki and Yerges-Armstrong, Laura M and Zhang, Yan and Snieder, Harold and Wanner, Christoph and B{\"o}ger, Carsten A and K{\"o}ttgen, Anna and Kronenberg, Florian and Pattaro, Cristian and Heid, Iris M} } @article {9112, title = {Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.}, journal = {Commun Biol}, volume = {5}, year = {2022}, month = {2022 Jun 13}, pages = {580}, abstract = {

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

}, keywords = {Creatinine, Diabetes Mellitus, Diabetic Nephropathies, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney}, issn = {2399-3642}, doi = {10.1038/s42003-022-03448-z}, author = {Winkler, Thomas W and Rasheed, Humaira and Teumer, Alexander and Gorski, Mathias and Rowan, Bryce X and Stanzick, Kira J and Thomas, Laurent F and Tin, Adrienne and Hoppmann, Anselm and Chu, Audrey Y and Tayo, Bamidele and Thio, Chris H L and Cusi, Daniele and Chai, Jin-Fang and Sieber, Karsten B and Horn, Katrin and Li, Man and Scholz, Markus and Cocca, Massimiliano and Wuttke, Matthias and van der Most, Peter J and Yang, Qiong and Ghasemi, Sahar and Nutile, Teresa and Li, Yong and Pontali, Giulia and G{\"u}nther, Felix and Dehghan, Abbas and Correa, Adolfo and Parsa, Afshin and Feresin, Agnese and de Vries, Aiko P J and Zonderman, Alan B and Smith, Albert V and Oldehinkel, Albertine J and De Grandi, Alessandro and Rosenkranz, Alexander R and Franke, Andre and Teren, Andrej and Metspalu, Andres and Hicks, Andrew A and Morris, Andrew P and T{\"o}njes, Anke and Morgan, Anna and Podgornaia, Anna I and Peters, Annette and K{\"o}rner, Antje and Mahajan, Anubha and Campbell, Archie and Freedman, Barry I and Spedicati, Beatrice and Ponte, Belen and Sch{\"o}ttker, Ben and Brumpton, Ben and Banas, Bernhard and Kr{\"a}mer, Bernhard K and Jung, Bettina and {\r A}svold, Bj{\o}rn Olav and Smith, Blair H and Ning, Boting and Penninx, Brenda W J H and Vanderwerff, Brett R and Psaty, Bruce M and Kammerer, Candace M and Langefeld, Carl D and Hayward, Caroline and Spracklen, Cassandra N and Robinson-Cohen, Cassianne and Hartman, Catharina A and Lindgren, Cecilia M and Wang, Chaolong and Sabanayagam, Charumathi and Heng, Chew-Kiat and Lanzani, Chiara and Khor, Chiea-Chuen and Cheng, Ching-Yu and Fuchsberger, Christian and Gieger, Christian and Shaffer, Christian M and Schulz, Christina-Alexandra and Willer, Cristen J and Chasman, Daniel I and Gudbjartsson, Daniel F and Ruggiero, Daniela and Toniolo, Daniela and Czamara, Darina and Porteous, David J and Waterworth, Dawn M and Mascalzoni, Deborah and Mook-Kanamori, Dennis O and Reilly, Dermot F and Daw, E Warwick and Hofer, Edith and Boerwinkle, Eric and Salvi, Erika and Bottinger, Erwin P and Tai, E-Shyong and Catamo, Eulalia and Rizzi, Federica and Guo, Feng and Rivadeneira, Fernando and Guilianini, Franco and Sveinbjornsson, Gardar and Ehret, Georg and Waeber, G{\'e}rard and Biino, Ginevra and Girotto, Giorgia and Pistis, Giorgio and Nadkarni, Girish N and Delgado, Graciela E and Montgomery, Grant W and Snieder, Harold and Campbell, Harry and White, Harvey D and Gao, He and Stringham, Heather M and Schmidt, Helena and Li, Hengtong and Brenner, Hermann and Holm, Hilma and Kirsten, Holgen and Kramer, Holly and Rudan, Igor and Nolte, Ilja M and Tzoulaki, Ioanna and Olafsson, Isleifur and Martins, Jade and Cook, James P and Wilson, James F and Halbritter, Jan and Felix, Janine F and Divers, Jasmin and Kooner, Jaspal S and Lee, Jeannette Jen-Mai and O{\textquoteright}Connell, Jeffrey and Rotter, Jerome I and Liu, Jianjun and Xu, Jie and Thiery, Joachim and Arnl{\"o}v, Johan and Kuusisto, Johanna and Jakobsdottir, Johanna and Tremblay, Johanne and Chambers, John C and Whitfield, John B and Gaziano, John M and Marten, Jonathan and Coresh, Josef and Jonas, Jost B and Mychaleckyj, Josyf C and Christensen, Kaare and Eckardt, Kai-Uwe and Mohlke, Karen L and Endlich, Karlhans and Dittrich, Katalin and Ryan, Kathleen A and Rice, Kenneth M and Taylor, Kent D and Ho, Kevin and Nikus, Kjell and Matsuda, Koichi and Strauch, Konstantin and Miliku, Kozeta and Hveem, Kristian and Lind, Lars and Wallentin, Lars and Yerges-Armstrong, Laura M and Raffield, Laura M and Phillips, Lawrence S and Launer, Lenore J and Lyytik{\"a}inen, Leo-Pekka and Lange, Leslie A and Citterio, Lorena and Klaric, Lucija and Ikram, M Arfan and Ising, Marcus and Kleber, Marcus E and Francescatto, Margherita and Concas, Maria Pina and Ciullo, Marina and Piratsu, Mario and Orho-Melander, Marju and Laakso, Markku and Loeffler, Markus and Perola, Markus and de Borst, Martin H and G{\"o}gele, Martin and Bianca, Martina La and Lukas, Mary Ann and Feitosa, Mary F and Biggs, Mary L and Wojczynski, Mary K and Kavousi, Maryam and Kanai, Masahiro and Akiyama, Masato and Yasuda, Masayuki and Nauck, Matthias and Waldenberger, Melanie and Chee, Miao-Li and Chee, Miao-Ling and Boehnke, Michael and Preuss, Michael H and Stumvoll, Michael and Province, Michael A and Evans, Michele K and O{\textquoteright}Donoghue, Michelle L and Kubo, Michiaki and K{\"a}h{\"o}nen, Mika and Kastarinen, Mika and Nalls, Mike A and Kuokkanen, Mikko and Ghanbari, Mohsen and Bochud, Murielle and Josyula, Navya Shilpa and Martin, Nicholas G and Tan, Nicholas Y Q and Palmer, Nicholette D and Pirastu, Nicola and Schupf, Nicole and Verweij, Niek and Hutri-K{\"a}h{\"o}nen, Nina and Mononen, Nina and Bansal, Nisha and Devuyst, Olivier and Melander, Olle and Raitakari, Olli T and Polasek, Ozren and Manunta, Paolo and Gasparini, Paolo and Mishra, Pashupati P and Sulem, Patrick and Magnusson, Patrik K E and Elliott, Paul and Ridker, Paul M and Hamet, Pavel and Svensson, Per O and Joshi, Peter K and Kovacs, Peter and Pramstaller, Peter P and Rossing, Peter and Vollenweider, Peter and van der Harst, Pim and Dorajoo, Rajkumar and Sim, Ralene Z H and Burkhardt, Ralph and Tao, Ran and Noordam, Raymond and M{\"a}gi, Reedik and Schmidt, Reinhold and de Mutsert, Ren{\'e}e and Rueedi, Rico and van Dam, Rob M and Carroll, Robert J and Gansevoort, Ron T and Loos, Ruth J F and Felicita, Sala Cinzia and Sedaghat, Sanaz and Padmanabhan, Sandosh and Freitag-Wolf, Sandra and Pendergrass, Sarah A and Graham, Sarah E and Gordon, Scott D and Hwang, Shih-Jen and Kerr, Shona M and Vaccargiu, Simona and Patil, Snehal B and Hallan, Stein and Bakker, Stephan J L and Lim, Su-Chi and Lucae, Susanne and Vogelezang, Suzanne and Bergmann, Sven and Corre, Tanguy and Ahluwalia, Tarunveer S and Lehtim{\"a}ki, Terho and Boutin, Thibaud S and Meitinger, Thomas and Wong, Tien-Yin and Bergler, Tobias and Rabelink, Ton J and Esko, T{\~o}nu and Haller, Toomas and Thorsteinsdottir, Unnur and V{\"o}lker, Uwe and Foo, Valencia Hui Xian and Salomaa, Veikko and Vitart, Veronique and Giedraitis, Vilmantas and Gudnason, Vilmundur and Jaddoe, Vincent W V and Huang, Wei and Zhang, Weihua and Wei, Wen Bin and Kiess, Wieland and M{\"a}rz, Winfried and Koenig, Wolfgang and Lieb, Wolfgang and G{\`a}o, Xin and Sim, Xueling and Wang, Ya Xing and Friedlander, Yechiel and Tham, Yih-Chung and Kamatani, Yoichiro and Okada, Yukinori and Milaneschi, Yuri and Yu, Zhi and Stark, Klaus J and Stefansson, Kari and B{\"o}ger, Carsten A and Hung, Adriana M and Kronenberg, Florian and K{\"o}ttgen, Anna and Pattaro, Cristian and Heid, Iris M} } @article {9093, title = {Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.}, journal = {Kidney Int}, year = {2022}, month = {2022 Jun 16}, abstract = {

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95\% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95\% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

}, issn = {1523-1755}, doi = {10.1016/j.kint.2022.05.021}, author = {Gorski, Mathias and Rasheed, Humaira and Teumer, Alexander and Thomas, Laurent F and Graham, Sarah E and Sveinbjornsson, Gardar and Winkler, Thomas W and G{\"u}nther, Felix and Stark, Klaus J and Chai, Jin-Fang and Tayo, Bamidele O and Wuttke, Matthias and Li, Yong and Tin, Adrienne and Ahluwalia, Tarunveer S and Arnl{\"o}v, Johan and {\r A}svold, Bj{\o}rn Olav and Bakker, Stephan J L and Banas, Bernhard and Bansal, Nisha and Biggs, Mary L and Biino, Ginevra and B{\"o}hnke, Michael and Boerwinkle, Eric and Bottinger, Erwin P and Brenner, Hermann and Brumpton, Ben and Carroll, Robert J and Chaker, Layal and Chalmers, John and Chee, Miao-Li and Chee, Miao-Ling and Cheng, Ching-Yu and Chu, Audrey Y and Ciullo, Marina and Cocca, Massimiliano and Cook, James P and Coresh, Josef and Cusi, Daniele and de Borst, Martin H and Degenhardt, Frauke and Eckardt, Kai-Uwe and Endlich, Karlhans and Evans, Michele K and Feitosa, Mary F and Franke, Andre and Freitag-Wolf, Sandra and Fuchsberger, Christian and Gampawar, Piyush and Gansevoort, Ron T and Ghanbari, Mohsen and Ghasemi, Sahar and Giedraitis, Vilmantas and Gieger, Christian and Gudbjartsson, Daniel F and Hallan, Stein and Hamet, Pavel and Hishida, Asahi and Ho, Kevin and Hofer, Edith and Holleczek, Bernd and Holm, Hilma and Hoppmann, Anselm and Horn, Katrin and Hutri-K{\"a}h{\"o}nen, Nina and Hveem, Kristian and Hwang, Shih-Jen and Ikram, M Arfan and Josyula, Navya Shilpa and Jung, Bettina and K{\"a}h{\"o}nen, Mika and Karabegovi{\'c}, Irma and Khor, Chiea-Chuen and Koenig, Wolfgang and Kramer, Holly and Kr{\"a}mer, Bernhard K and Kuhnel, Brigitte and Kuusisto, Johanna and Laakso, Markku and Lange, Leslie A and Lehtim{\"a}ki, Terho and Li, Man and Lieb, Wolfgang and Lind, Lars and Lindgren, Cecilia M and Loos, Ruth J F and Lukas, Mary Ann and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Matias-Garcia, Pamela R and Meisinger, Christa and Meitinger, Thomas and Melander, Olle and Milaneschi, Yuri and Mishra, Pashupati P and Mononen, Nina and Morris, Andrew P and Mychaleckyj, Josyf C and Nadkarni, Girish N and Naito, Mariko and Nakatochi, Masahiro and Nalls, Mike A and Nauck, Matthias and Nikus, Kjell and Ning, Boting and Nolte, Ilja M and Nutile, Teresa and O{\textquoteright}Donoghue, Michelle L and O{\textquoteright}Connell, Jeffrey and Olafsson, Isleifur and Orho-Melander, Marju and Parsa, Afshin and Pendergrass, Sarah A and Penninx, Brenda W J H and Pirastu, Mario and Preuss, Michael H and Psaty, Bruce M and Raffield, Laura M and Raitakari, Olli T and Rheinberger, Myriam and Rice, Kenneth M and Rizzi, Federica and Rosenkranz, Alexander R and Rossing, Peter and Rotter, Jerome I and Ruggiero, Daniela and Ryan, Kathleen A and Sabanayagam, Charumathi and Salvi, Erika and Schmidt, Helena and Schmidt, Reinhold and Scholz, Markus and Sch{\"o}ttker, Ben and Schulz, Christina-Alexandra and Sedaghat, Sanaz and Shaffer, Christian M and Sieber, Karsten B and Sim, Xueling and Sims, Mario and Snieder, Harold and Stanzick, Kira J and Thorsteinsdottir, Unnur and Stocker, Hannah and Strauch, Konstantin and Stringham, Heather M and Sulem, Patrick and Szymczak, Silke and Taylor, Kent D and Thio, Chris H L and Tremblay, Johanne and Vaccargiu, Simona and van der Harst, Pim and van der Most, Peter J and Verweij, Niek and V{\"o}lker, Uwe and Wakai, Kenji and Waldenberger, Melanie and Wallentin, Lars and Wallner, Stefan and Wang, Judy and Waterworth, Dawn M and White, Harvey D and Willer, Cristen J and Wong, Tien-Yin and Woodward, Mark and Yang, Qiong and Yerges-Armstrong, Laura M and Zimmermann, Martina and Zonderman, Alan B and Bergler, Tobias and Stefansson, Kari and B{\"o}ger, Carsten A and Pattaro, Cristian and K{\"o}ttgen, Anna and Kronenberg, Florian and Heid, Iris M} } @article {9385, title = {Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.}, journal = {medRxiv}, year = {2023}, month = {2023 Mar 31}, abstract = {

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7\% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5{\texttimes}10 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

}, doi = {10.1101/2023.03.31.23287839}, author = {Suzuki, Ken and Hatzikotoulas, Konstantinos and Southam, Lorraine and Taylor, Henry J and Yin, Xianyong and Lorenz, Kim M and Mandla, Ravi and Huerta-Chagoya, Alicia and Rayner, Nigel W and Bocher, Ozvan and Ana Luiza de, S V Arruda and Sonehara, Kyuto and Namba, Shinichi and Lee, Simon S K and Preuss, Michael H and Petty, Lauren E and Schroeder, Philip and Vanderwerff, Brett and Kals, Mart and Bragg, Fiona and Lin, Kuang and Guo, Xiuqing and Zhang, Weihua and Yao, Jie and Kim, Young Jin and Graff, Mariaelisa and Takeuchi, Fumihiko and Nano, Jana and Lamri, Amel and Nakatochi, Masahiro and Moon, Sanghoon and Scott, Robert A and Cook, James P and Lee, Jung-Jin and Pan, Ian and Taliun, Daniel and Parra, Esteban J and Chai, Jin-Fang and Bielak, Lawrence F and Tabara, Yasuharu and Hai, Yang and Thorleifsson, Gudmar and Grarup, Niels and Sofer, Tamar and Wuttke, Matthias and Sarnowski, Chloe and Gieger, Christian and Nousome, Darryl and Trompet, Stella and Kwak, Soo-Heon and Long, Jirong and Sun, Meng and Tong, Lin and Chen, Wei-Min and Nongmaithem, Suraj S and Noordam, Raymond and Lim, Victor J Y and Tam, Claudia H T and Joo, Yoonjung Yoonie and Chen, Chien-Hsiun and Raffield, Laura M and Prins, Bram Peter and Nicolas, Aude and Yanek, Lisa R and Chen, Guanjie and Brody, Jennifer A and Kabagambe, Edmond and An, Ping and Xiang, Anny H and Choi, Hyeok Sun and Cade, Brian E and Tan, Jingyi and Alaine Broadaway, K and Williamson, Alice and Kamali, Zoha and Cui, Jinrui and Adair, Linda S and Adeyemo, Adebowale and Aguilar-Salinas, Carlos A and Ahluwalia, Tarunveer S and Anand, Sonia S and Bertoni, Alain and Bork-Jensen, Jette and Brandslund, Ivan and Buchanan, Thomas A and Burant, Charles F and Butterworth, Adam S and Canouil, Micka{\"e}l and Chan, Juliana C N and Chang, Li-Ching and Chee, Miao-Li and Chen, Ji and Chen, Shyh-Huei and Chen, Yuan-Tsong and Chen, Zhengming and Chuang, Lee-Ming and Cushman, Mary and Danesh, John and Das, Swapan K and Janaka de Silva, H and Dedoussis, George and Dimitrov, Latchezar and Doumatey, Ayo P and Du, Shufa and Duan, Qing and Eckardt, Kai-Uwe and Emery, Leslie S and Evans, Daniel S and Evans, Michele K and Fischer, Krista and Floyd, James S and Ford, Ian and Franco, Oscar H and Frayling, Timothy M and Freedman, Barry I and Genter, Pauline and Gerstein, Hertzel C and Giedraitis, Vilmantas and Gonz{\'a}lez-Villalpando, Clicerio and Gonzalez-Villalpando, Maria Elena and Gordon-Larsen, Penny and Gross, Myron and Guare, Lindsay A and Hackinger, Sophie and Han, Sohee and Hattersley, Andrew T and Herder, Christian and Horikoshi, Momoko and Howard, Annie-Green and Hsueh, Willa and Huang, Mengna and Huang, Wei and Hung, Yi-Jen and Hwang, Mi Yeong and Hwu, Chii-Min and Ichihara, Sahoko and Ikram, Mohammad Arfan and Ingelsson, Martin and Islam, Md Tariqul and Isono, Masato and Jang, Hye-Mi and Jasmine, Farzana and Jiang, Guozhi and Jonas, Jost B and J{\o}rgensen, Torben and Kandeel, Fouad R and Kasturiratne, Anuradhani and Katsuya, Tomohiro and Kaur, Varinderpal and Kawaguchi, Takahisa and Keaton, Jacob M and Kho, Abel N and Khor, Chiea-Chuen and Kibriya, Muhammad G and Kim, Duk-Hwan and Kronenberg, Florian and Kuusisto, Johanna and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Kyung Min and Lee, Myung-Shik and Lee, Nanette R and Leong, Aaron and Li, Liming and Li, Yun and Li-Gao, Ruifang and Lithgart, Symen and Lindgren, Cecilia M and Linneberg, Allan and Liu, Ching-Ti and Liu, Jianjun and Locke, Adam E and Louie, Tin and Luan, Jian{\textquoteright}an and Luk, Andrea O and Luo, Xi and Lv, Jun and Lynch, Julie A and Lyssenko, Valeriya and Maeda, Shiro and Mamakou, Vasiliki and Mansuri, Sohail Rafik and Matsuda, Koichi and Meitinger, Thomas and Metspalu, Andres and Mo, Huan and Morris, Andrew D and Nadler, Jerry L and Nalls, Michael A and Nayak, Uma and Ntalla, Ioanna and Okada, Yukinori and Orozco, Lorena and Patel, Sanjay R and Patil, Snehal and Pei, Pei and Pereira, Mark A and Peters, Annette and Pirie, Fraser J and Polikowsky, Hannah G and Porneala, Bianca and Prasad, Gauri and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Roden, Michael and Rohde, Rebecca and Roll, Katheryn and Sabanayagam, Charumathi and Sandow, Kevin and Sankareswaran, Alagu and Sattar, Naveed and Sch{\"o}nherr, Sebastian and Shahriar, Mohammad and Shen, Botong and Shi, Jinxiu and Shin, Dong Mun and Shojima, Nobuhiro and Smith, Jennifer A and So, Wing Yee and Stan{\v c}{\'a}kov{\'a}, Alena and Steinthorsdottir, Valgerdur and Stilp, Adrienne M and Strauch, Konstantin and Taylor, Kent D and Thorand, Barbara and Thorsteinsdottir, Unnur and Tomlinson, Brian and Tran, Tam C and Tsai, Fuu-Jen and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and Udler, Miriam S and Valladares-Salgado, Adan and van Dam, Rob M and van Klinken, Jan B and Varma, Rohit and Wacher-Rodarte, Niels and Wheeler, Eleanor and Wickremasinghe, Ananda R and van Dijk, Ko Willems and Witte, Daniel R and Yajnik, Chittaranjan S and Yamamoto, Ken and Yamamoto, Kenichi and Yoon, Kyungheon and Yu, Canqing and Yuan, Jian-Min and Yusuf, Salim and Zawistowski, Matthew and Zhang, Liang and Zheng, Wei and Project, Biobank Japan and BioBank, Penn Medicine and Center, Regeneron Genetics and Consortium, eMERGE and Raffel, Leslie J and Igase, Michiya and Ipp, Eli and Redline, Susan and Cho, Yoon Shin and Lind, Lars and Province, Michael A and Fornage, Myriam and Hanis, Craig L and Ingelsson, Erik and Zonderman, Alan B and Psaty, Bruce M and Wang, Ya-Xing and Rotimi, Charles N and Becker, Diane M and Matsuda, Fumihiko and Liu, Yongmei and Yokota, Mitsuhiro and Kardia, Sharon L R and Peyser, Patricia A and Pankow, James S and Engert, James C and Bonnefond, Am{\'e}lie and Froguel, Philippe and Wilson, James G and Sheu, Wayne H H and Wu, Jer-Yuarn and Geoffrey Hayes, M and Ma, Ronald C W and Wong, Tien-Yin and Mook-Kanamori, Dennis O and Tuomi, Tiinamaija and Chandak, Giriraj R and Collins, Francis S and Bharadwaj, Dwaipayan and Par{\'e}, Guillaume and Sale, Mich{\`e}le M and Ahsan, Habibul and Motala, Ayesha A and Shu, Xiao-Ou and Park, Kyong-Soo and Jukema, J Wouter and Cruz, Miguel and Chen, Yii-Der Ida and Rich, Stephen S and McKean-Cowdin, Roberta and Grallert, Harald and Cheng, Ching-Yu and Ghanbari, Mohsen and Tai, E-Shyong and Dupuis, Jos{\'e}e and Kato, Norihiro and Laakso, Markku and K{\"o}ttgen, Anna and Koh, Woon-Puay and Bowden, Donald W and Palmer, Colin N A and Kooner, Jaspal S and Kooperberg, Charles and Liu, Simin and North, Kari E and Saleheen, Danish and Hansen, Torben and Pedersen, Oluf and Wareham, Nicholas J and Lee, Juyoung and Kim, Bong-Jo and Millwood, Iona Y and Walters, Robin G and Stefansson, Kari and Goodarzi, Mark O and Mohlke, Karen L and Langenberg, Claudia and Haiman, Christopher A and Loos, Ruth J F and Florez, Jose C and Rader, Daniel J and Ritchie, Marylyn D and Z{\"o}llner, Sebastian and M{\"a}gi, Reedik and Denny, Joshua C and Yamauchi, Toshimasa and Kadowaki, Takashi and Chambers, John C and Ng, Maggie C Y and Sim, Xueling and Below, Jennifer E and Tsao, Philip S and Chang, Kyong-Mi and McCarthy, Mark I and Meigs, James B and Mahajan, Anubha and Spracklen, Cassandra N and Mercader, Josep M and Boehnke, Michael and Rotter, Jerome I and Vujkovic, Marijana and Voight, Benjamin F and Morris, Andrew P and Zeggini, Eleftheria} } @article {9619, title = {Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.}, journal = {Nature}, year = {2024}, month = {2024 Feb 19}, abstract = {

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7\% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 {\texttimes} 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

}, issn = {1476-4687}, doi = {10.1038/s41586-024-07019-6}, author = {Suzuki, Ken and Hatzikotoulas, Konstantinos and Southam, Lorraine and Taylor, Henry J and Yin, Xianyong and Lorenz, Kim M and Mandla, Ravi and Huerta-Chagoya, Alicia and Melloni, Giorgio E M and Kanoni, Stavroula and Rayner, Nigel W and Bocher, Ozvan and Arruda, Ana Luiza and Sonehara, Kyuto and Namba, Shinichi and Lee, Simon S K and Preuss, Michael H and Petty, Lauren E and Schroeder, Philip and Vanderwerff, Brett and Kals, Mart and Bragg, Fiona and Lin, Kuang and Guo, Xiuqing and Zhang, Weihua and Yao, Jie and Kim, Young Jin and Graff, Mariaelisa and Takeuchi, Fumihiko and Nano, Jana and Lamri, Amel and Nakatochi, Masahiro and Moon, Sanghoon and Scott, Robert A and Cook, James P and Lee, Jung-Jin and Pan, Ian and Taliun, Daniel and Parra, Esteban J and Chai, Jin-Fang and Bielak, Lawrence F and Tabara, Yasuharu and Hai, Yang and Thorleifsson, Gudmar and Grarup, Niels and Sofer, Tamar and Wuttke, Matthias and Sarnowski, Chloe and Gieger, Christian and Nousome, Darryl and Trompet, Stella and Kwak, Soo-Heon and Long, Jirong and Sun, Meng and Tong, Lin and Chen, Wei-Min and Nongmaithem, Suraj S and Noordam, Raymond and Lim, Victor J Y and Tam, Claudia H T and Joo, Yoonjung Yoonie and Chen, Chien-Hsiun and Raffield, Laura M and Prins, Bram Peter and Nicolas, Aude and Yanek, Lisa R and Chen, Guanjie and Brody, Jennifer A and Kabagambe, Edmond and An, Ping and Xiang, Anny H and Choi, Hyeok Sun and Cade, Brian E and Tan, Jingyi and Broadaway, K Alaine and Williamson, Alice and Kamali, Zoha and Cui, Jinrui and Thangam, Manonanthini and Adair, Linda S and Adeyemo, Adebowale and Aguilar-Salinas, Carlos A and Ahluwalia, Tarunveer S and Anand, Sonia S and Bertoni, Alain and Bork-Jensen, Jette and Brandslund, Ivan and Buchanan, Thomas A and Burant, Charles F and Butterworth, Adam S and Canouil, Micka{\"e}l and Chan, Juliana C N and Chang, Li-Ching and Chee, Miao-Li and Chen, Ji and Chen, Shyh-Huei and Chen, Yuan-Tsong and Chen, Zhengming and Chuang, Lee-Ming and Cushman, Mary and Danesh, John and Das, Swapan K and de Silva, H Janaka and Dedoussis, George and Dimitrov, Latchezar and Doumatey, Ayo P and Du, Shufa and Duan, Qing and Eckardt, Kai-Uwe and Emery, Leslie S and Evans, Daniel S and Evans, Michele K and Fischer, Krista and Floyd, James S and Ford, Ian and Franco, Oscar H and Frayling, Timothy M and Freedman, Barry I and Genter, Pauline and Gerstein, Hertzel C and Giedraitis, Vilmantas and Gonz{\'a}lez-Villalpando, Clicerio and Gonzalez-Villalpando, Maria Elena and Gordon-Larsen, Penny and Gross, Myron and Guare, Lindsay A and Hackinger, Sophie and Hakaste, Liisa and Han, Sohee and Hattersley, Andrew T and Herder, Christian and Horikoshi, Momoko and Howard, Annie-Green and Hsueh, Willa and Huang, Mengna and Huang, Wei and Hung, Yi-Jen and Hwang, Mi Yeong and Hwu, Chii-Min and Ichihara, Sahoko and Ikram, Mohammad Arfan and Ingelsson, Martin and Islam, Md Tariqul and Isono, Masato and Jang, Hye-Mi and Jasmine, Farzana and Jiang, Guozhi and Jonas, Jost B and J{\o}rgensen, Torben and Kamanu, Frederick K and Kandeel, Fouad R and Kasturiratne, Anuradhani and Katsuya, Tomohiro and Kaur, Varinderpal and Kawaguchi, Takahisa and Keaton, Jacob M and Kho, Abel N and Khor, Chiea-Chuen and Kibriya, Muhammad G and Kim, Duk-Hwan and Kronenberg, Florian and Kuusisto, Johanna and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Kyung Min and Lee, Myung-Shik and Lee, Nanette R and Leong, Aaron and Li, Liming and Li, Yun and Li-Gao, Ruifang and Ligthart, Symen and Lindgren, Cecilia M and Linneberg, Allan and Liu, Ching-Ti and Liu, Jianjun and Locke, Adam E and Louie, Tin and Luan, Jian{\textquoteright}an and Luk, Andrea O and Luo, Xi and Lv, Jun and Lynch, Julie A and Lyssenko, Valeriya and Maeda, Shiro and Mamakou, Vasiliki and Mansuri, Sohail Rafik and Matsuda, Koichi and Meitinger, Thomas and Melander, Olle and Metspalu, Andres and Mo, Huan and Morris, Andrew D and Moura, Filipe A and Nadler, Jerry L and Nalls, Michael A and Nayak, Uma and Ntalla, Ioanna and Okada, Yukinori and Orozco, Lorena and Patel, Sanjay R and Patil, Snehal and Pei, Pei and Pereira, Mark A and Peters, Annette and Pirie, Fraser J and Polikowsky, Hannah G and Porneala, Bianca and Prasad, Gauri and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Roden, Michael and Rohde, Rebecca and Roll, Katheryn and Sabanayagam, Charumathi and Sandow, Kevin and Sankareswaran, Alagu and Sattar, Naveed and Sch{\"o}nherr, Sebastian and Shahriar, Mohammad and Shen, Botong and Shi, Jinxiu and Shin, Dong Mun and Shojima, Nobuhiro and Smith, Jennifer A and So, Wing Yee and Stan{\v c}{\'a}kov{\'a}, Alena and Steinthorsdottir, Valgerdur and Stilp, Adrienne M and Strauch, Konstantin and Taylor, Kent D and Thorand, Barbara and Thorsteinsdottir, Unnur and Tomlinson, Brian and Tran, Tam C and Tsai, Fuu-Jen and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and Udler, Miriam S and Valladares-Salgado, Adan and van Dam, Rob M and van Klinken, Jan B and Varma, Rohit and Wacher-Rodarte, Niels and Wheeler, Eleanor and Wickremasinghe, Ananda R and van Dijk, Ko Willems and Witte, Daniel R and Yajnik, Chittaranjan S and Yamamoto, Ken and Yamamoto, Kenichi and Yoon, Kyungheon and Yu, Canqing and Yuan, Jian-Min and Yusuf, Salim and Zawistowski, Matthew and Zhang, Liang and Zheng, Wei and Raffel, Leslie J and Igase, Michiya and Ipp, Eli and Redline, Susan and Cho, Yoon Shin and Lind, Lars and Province, Michael A and Fornage, Myriam and Hanis, Craig L and Ingelsson, Erik and Zonderman, Alan B and Psaty, Bruce M and Wang, Ya-Xing and Rotimi, Charles N and Becker, Diane M and Matsuda, Fumihiko and Liu, Yongmei and Yokota, Mitsuhiro and Kardia, Sharon L R and Peyser, Patricia A and Pankow, James S and Engert, James C and Bonnefond, Am{\'e}lie and Froguel, Philippe and Wilson, James G and Sheu, Wayne H H and Wu, Jer-Yuarn and Hayes, M Geoffrey and Ma, Ronald C W and Wong, Tien-Yin and Mook-Kanamori, Dennis O and Tuomi, Tiinamaija and Chandak, Giriraj R and Collins, Francis S and Bharadwaj, Dwaipayan and Par{\'e}, Guillaume and Sale, Mich{\`e}le M and Ahsan, Habibul and Motala, Ayesha A and Shu, Xiao-Ou and Park, Kyong-Soo and Jukema, J Wouter and Cruz, Miguel and Chen, Yii-Der Ida and Rich, Stephen S and McKean-Cowdin, Roberta and Grallert, Harald and Cheng, Ching-Yu and Ghanbari, Mohsen and Tai, E-Shyong and Dupuis, Jos{\'e}e and Kato, Norihiro and Laakso, Markku and K{\"o}ttgen, Anna and Koh, Woon-Puay and Bowden, Donald W and Palmer, Colin N A and Kooner, Jaspal S and Kooperberg, Charles and Liu, Simin and North, Kari E and Saleheen, Danish and Hansen, Torben and Pedersen, Oluf and Wareham, Nicholas J and Lee, Juyoung and Kim, Bong-Jo and Millwood, Iona Y and Walters, Robin G and Stefansson, Kari and Ahlqvist, Emma and Goodarzi, Mark O and Mohlke, Karen L and Langenberg, Claudia and Haiman, Christopher A and Loos, Ruth J F and Florez, Jose C and Rader, Daniel J and Ritchie, Marylyn D and Z{\"o}llner, Sebastian and M{\"a}gi, Reedik and Marston, Nicholas A and Ruff, Christian T and van Heel, David A and Finer, Sarah and Denny, Joshua C and Yamauchi, Toshimasa and Kadowaki, Takashi and Chambers, John C and Ng, Maggie C Y and Sim, Xueling and Below, Jennifer E and Tsao, Philip S and Chang, Kyong-Mi and McCarthy, Mark I and Meigs, James B and Mahajan, Anubha and Spracklen, Cassandra N and Mercader, Josep M and Boehnke, Michael and Rotter, Jerome I and Vujkovic, Marijana and Voight, Benjamin F and Morris, Andrew P and Zeggini, Eleftheria} }